Historically natural products from terrestrial plants and microbes have provided humankind with some of our most novel and valued treatments for infectious diseases, in addition to providing new targets for the rational design of synthetic drugs. The key objectives to be addressed by this project include: 1. The characterization of novel marine natural product leads for the treatment of HIV-1 and AIDS OI from marine invertebrates, algae and microbes. This involves the bioassay guided isolation of active extracts to be accomplished utilizing several significant AIDS OI including C. albicans, C. neoformans, S. aureus, MRS and Mtb. Marine samples will be identified and dereplicated using a combination of traditional taxonomic techniques combined with molecular biology, secondary metabolism and database analysis. Purified natural products will be examined for activity against both wild type and resistant strains of HIV-1 and AIDS OI. Structure determination will be completed using spectroscopic methods utilized in combination with molecular modeling and chemical methods. In particular detailed high field NMR studies will be completed for noncrystalline materials and X-ray crystallography will be utilized for materials that can successfully be crystallized. 2. The optimization of marine natural product leads identified in aim 1 will be completed using semisynthesis and biotransformation studies. The rational modification of marine products will be based on a combination of SAR for the structural class, antiinfective activity and a statistical analysis of pharmacophores found in clinically utilized drugs. Materials will be sourced through well established relationships with academic programs in Indonesia, Jamaica, Egypt, Saudi Arabia, and Nigeria in addition to the evaluation of domestic samples. These areas broadly represent the greatest marine biodiversity available on the planet and a well organized repository of crude extracts, initial column fractions as well as pure natural, semisynthetic and synthetic products will be maintained for future evaluation against emerging or remerging/resistant infectious diseases.